http://hdl.handle.net/10366/133043 Thu, 30 Apr 2026 19:33:40 GMT 2026-04-30T19:33:40Z http://hdl.handle.net/10366/170354 [ES] Las RASopatías asociadas a alteraciones en los genes NF1 y SPRED1 presentan una marcada heterogeneidad clínica y molecular, donde el principal obstáculo tras el diagnóstico genético es la interpretación funcional de las variantes identificadas. Con el objetivo de superar este desafío, la presente tesis doctoral ha creado un flujo de trabajo experimental multidisciplinar que combina el análisis de variantes en NF1 y SPRED1 reportadas en bases de datos públicas y de pacientes de la DIERCyL, el modelado estructural y de estabilidad proteica in silico, la señalización celular, proliferación, y morfometría en las líneas celulares HEK293T y NIH3T3. Los análisis de las bases de datos genéticas identificaron hotspots estructurales críticos en la proteína neurofibromina (CSRD, GRD y Armadillo1), mientras que las variantes en SPRED1 mostraron una distribución homogénea, sugiriendo mecanismos patogénicos distintos. En el caso de las variantes en NF1 y SPRED1 de los pacientes, el análisis energético reveló un espectro continuo en neurofibromina que va desde haploinsuficiencia hasta dominancia negativa en truncantes tardías, mientras que en SPRED1 predominó la pérdida de función. Los ensayos celulares in vitro, mostraron dinámicas de señalización celular diferentes según el tipo de variante analizada en los genes NF1 y SPRED1. En particular, la hiperactivación de ERK emergió como el evento molecular más determinante para la patogenicidad de las variantes. La coactivación de p38 identificó variantes de mayor severidad clínica, mientras que la relación inversa p- ERK/p-AKT(Ser473) reveló un circuito de retroalimentación negativa entre las rutas de señalización MAPK y PI3K/AKT. Los ensayos de proliferación celular y el análisis cuantitativo del tamaño celular revelaron fenotipos consistentes con el grado de desregulación de MAPK, proporcionando biomarcadores fenotípicos adicionales para diferenciar entre variantes patogénicas y benignas en ambos genes. La relevancia tisular de HEK293T (contextos epiteliales/neuroectodérmicos) y NIH3T3 (mesenquimales) permitió reproducir la heterogeneidad clínica observada en pacientes. Los resultados de esta tesis doctoral han permitido reclasificar variantes de significado incierto en ambos genes e identificar la hiperactivación de ERK como diana terapéutica prioritaria, apoyando el uso de inhibidores de MEK en contextos compatibles con esta desregulación. En conjunto, este trabajo establece un marco integral para la interpretación funcional de variantes en RASopatías y para el desarrollo de futuras estrategias de medicina personalizada.; [EN] RASopathies associated with alterations in the NF1 and SPRED1 genes exhibit marked clinical and molecular heterogeneity, where the main challenge after genetic diagnosis lies in the functional interpretation of the identified variants. To address this issue, this doctoral thesis established a multidisciplinary experimental workflow that integrates the analysis of NF1 and SPRED1 variants reported in public databases and in patients from the DIERCyL cohort, together with in silico structural and protein-stability modeling, cellular signaling assays, proliferation studies, and morphometric analyses in HEK293T and NIH3T3 cell lines. Database analyses identified critical structural hotspots in neurofibromin (CSRD, GRD, and Armadillo1), whereas SPRED1 variants showed a more homogeneous distribution, suggesting distinct pathogenic mechanisms. In patient-derived NF1 and SPRED1 variants, energy-based analyses revealed a continuous spectrum in neurofibromin, ranging from haploinsufficiency to dominant-negative effects in late truncating variants, while SPRED1 alterations predominantly showed loss-of-function behavior. The in vitro cellular assays revealed distinct signaling dynamics depending on the type of variant analyzed in NF1 and SPRED1. Notably, ERK hyperactivation emerged as the most determinant molecular event for pathogenicity. Co-activation of p38 identified variants associated with more severe clinical outcomes, whereas the inverse p-ERK/p- AKT(Ser473) relationship revealed a negative feedback circuit between the MAPK and PI3K/AKT pathways. Cell-proliferation assays and quantitative cell-size analyses uncovered phenotypes consistent with the degree of MAPK deregulation, providing additional phenotypic biomarkers to discriminate between pathogenic and benign variants in both genes. The tissue relevance of HEK293T (epithelial/neuroectodermal contexts) and NIH3T3 (mesenchymal) cells allowed us to recapitulate the clinical heterogeneity observed in patients. The results of this doctoral thesis enabled the reclassification of variants of uncertain significance in both genes and identified ERK hyperactivation as a priority therapeutic target, supporting the use of MEK inhibitors in contexts consistent with this dysregulation. Taken together, this work establishes a comprehensive framework for the functional interpretation of variants in RASopathies and for the development of future personalizedmedicine strategies. Wed, 01 Jan 2025 00:00:00 GMT http://hdl.handle.net/10366/170354 2025-01-01T00:00:00Z http://hdl.handle.net/10366/170001 [ES] La enfermedad de Huntington (EH) es un trastorno neurodegenerativo que concurre con la acumulación de la proteína huntingtina mutante (mtHTT) en el cerebro. Aunque tradicionalmente se ha asociado con la pérdida progresiva de neuronas principalmente del estriado y en menor proporción en la corteza, evidencias recientes sugieren que los astrocitos también desempeñan un papel crucial en la etiogénesis y evolución de la enfermedad. En la EH, la disfunción del proceso autofágico contribuye a la acumulación de agregados de mtHTT, aunque aún se debate si los astrocitos participan activamente en esta alteración. La regulación de la autofagia, mediada por el sistema cannabinoide, emerge así como un mecanismo clave para comprender el progreso de la EH. Sin embargo, los efectos de los cannabinoides en esta enfermedad son controvertidos y parecen depender del tipo celular involucrado. En esta tesis doctoral, empleamos un enfoque genético mediado por partículas virales, para inducir de manera selectiva la expresión de HTT en astrocitos. El análisis de la proteostasis de agregación de HTT astrocítica in vitro, demostró que la activación cannabinoide por Δ9- tetrahidrocannabinol (THC) induce un proceso autofágico selectivo. Este medió de forma eficiente la disminución de agregados de mtHTT, así como la preservación de la función mitocondrial, mediada por mitofagia. In vivo, la expresión de mtHTT astrocítica reprodujo características clave de la EH, como gliosis, neurodegeneración y deterioro motor, que fueron prevenidas por THC. Nuestros hallazgos desafían la visión exclusivamente neurocéntrica de la EH y demuestran la relevancia patológica de la agregación de mtHTT astrocítica. El manejo de esta por el sistema cannabinoide resalta el potencial terapéutico de intervenir sobre la función astrocítica en el tratamiento de enfermedades neurodegenerativas. Wed, 01 Jan 2025 00:00:00 GMT http://hdl.handle.net/10366/170001 2025-01-01T00:00:00Z http://hdl.handle.net/10366/169995 [ES] Belantamab mafodotin (belamaf) es un conjugado anticuerpo-fármaco dirigido contra BCMA con una actividad prometedora para el mieloma múltiple en recaída/refractario (RRMM) en regímenes basados en combinaciones. Sin embargo, debido a su reciente introducción, aún no se conocen bien sus mecanismos de resistencia. Esta tesis tuvo como objetivo evaluar el potencial terapéutico de las combinaciones basadas en belamaf y esclarecer los mecanismos implicados en la resistencia adquirida, mediante modelos preclínicos y el análisis de datos clínicos. La combinación de belamaf con daratumumab mostró sinergia en líneas celulares de mieloma múltiple y modelos murinos, aumentando la citotoxicidad a dosis bajas y promoviendo la muerte celular inmunogénica. Para modelar la resistencia, se generaron líneas celulares resistentes a belamaf y se sometieron a análisis transcriptómicos y genómicos, que revelaron pérdida de expresión de BCMA y activación de vías asociadas a la respuesta inmune, la fosforilación oxidativa y la regulación del ciclo celular. La validación funcional demostró que la sobreexpresión estable de BCMA restauró completamente la sensibilidad a belamaf en uno de los modelos, mientras que en el otro solo se observó una recuperación parcial, lo que sugiere la implicación de mecanismos adicionales. Para explorar el impacto inmunológico de belamaf en un contexto clínico, se analizaron los perfiles inmunes de los pacientes incluidos en el ensayo GEM Bela-VRd, que evalúa la adición de belamaf al esquema estándar VRd (bortezomib, lenalidomida, dexametasona) en pacientes con mieloma múltiple de nuevo diagnóstico y candidatos a trasplante. Se observó una reducción de linfocitos totales y células T CD4+ en sangre periférica, sin evidencias de un fenotipo exhausto en las células efectoras. Los análisis exploratorios también mostraron una disminución progresiva de las células plasmáticas malignas y un aumento en la expresión de marcadores asociados con muerte celular inmunogénica. El recuento absoluto de linfocitos totales, células T CD8+ y células NK surgió como un posible biomarcador de respuesta, con valores más altos asociados a respuestas más profundas, tanto en el ciclo 3 como al final de la inducción. En conjunto, estos hallazgos aportan una justificación preclínica sólida para el desarrollo clínico de la combinación de daratumumab y belamaf. Paralelamente, nuestros análisis de inmunomonitorización en el ensayo GEM Bela-VRd subrayan la relevancia de seguir el perfil inmune durante el tratamiento, ofreciendo biomarcadores potenciales para guiar la evaluación de la respuesta en el mieloma múltiple.; [EN] Belantamab mafodotin (belamaf) is an antibody-drug conjugate targeting BCMA with promising activity for relapsed/refractory multiple myeloma (RRMM) in combination-based regimens. However, due to its recent introduction, its resistance mechanisms are not yet fully understood. This thesis aimed to evaluate the therapeutic potential of new belamaf-based combinations and to elucidate mechanisms underlying acquired resistance, both through preclinical models and clinical data analysis. The combination of belamaf and daratumumab exhibited strong synergy in multiple myeloma cell lines and mouse models, enhancing cytotoxicity at low doses and promoting immunogenic cell death. To model resistance, belamaf-resistant cell lines were generated and subjected to transcriptomic and genomic profiling, revealing BCMA loss, and activation of immune response, oxidative phosphorylation, and cell cycle regulation pathways. Functional validation demonstrated that stable overexpression of BCMA fully restored belamaf sensitivity in one model, while only partial restoration was observed in the other model of resistance, suggesting the implication of additional mechanisms. To further explore the immunological impact of belamaf in a clinical setting, we analyzed immune profiles from patients enrolled in the GEM Bela-VRd trial, which investigates the addition of belamaf to the standard VRd regimen (bortezomib, lenalidomide, dexamethasone) in newly diagnosed transplant-eligible MM patients. We observed a reduction in total lymphocyte and CD4+ T cells in peripheral blood, without producing an exhausted phenotype in effector cells. Exploratory analyses also showed a progressive reduction in malignant plasma cells and increased expression of markers associated with immunogenic cell death. Absolute counts of total lymphocytes, CD8+ T cells and NK cells emerged as potential biomarkers of response, with higher counts associated with deeper responses, both at cycle 3 and end of induction therapy. Together, these findings provide a strong preclinical rationale for the clinical development of the daratumumab and belamaf combination. In parallel, our immunomonitoring analyses within the GEM Bela-VRd clinical trial highlight the relevance of tracking immune profiles during treatment, offering potential biomarkers to guide response assessment in multiple myeloma. Wed, 01 Jan 2025 00:00:00 GMT http://hdl.handle.net/10366/169995 2025-01-01T00:00:00Z http://hdl.handle.net/10366/169721 [EN] This paper is concerned with the application of a Hybrid Algorithm (HA) to the determination of the Thermodynamic Activation Parameters (ATP) of a kinetic system of first order consecutive reactions. The 8 ATP’s parameters involved in the Arrhenius and Eyring equations have been directly determined from the non-isothermal kinetic data without prior knowledge of the rate constants. AH is constituted by a combination of two algorithms based on different mathematical principles which are sequentially applied. In a first step, a “soft modeling” method of Artificial Neural Networks (ANN) is applied and the obtained values of ATP’s parameters are used as initial estimates of a new optimization algorithm (AGDC) applied in a second stage to improve the values of the final parameters. The great success of HA is the efficient resolution of the ambiguity of the results obtained by ANN. In addition, comparing with the classic algorithms, which present the known weak points, HA offers important advantages: (a) the lack of necessity to know a priori the initial estimates since they are calculated from ANN application, (b) the low probability of being trapped at local minima, saddle points, etc. by means of the exhaustive control and suitable correction of the movement vector during the optimization process, and (c) the simultaneous determination of a higher number of parameters endowed with very different orders of magnitude. Thu, 01 Jan 2015 00:00:00 GMT http://hdl.handle.net/10366/169721 2015-01-01T00:00:00Z http://hdl.handle.net/10366/169483 [EN]This work describes the successful melt infiltration of poly(butylene succinate) (PBS) and poly(butylene adipate) (PBA) within 70 nm diameter anodic aluminum oxide (AAO) templates. The infiltrated samples were characterized by SEM, Raman, and FTIR spectroscopy. The crystallization behaviors and crystalline structures of both polymers, bulk and confined, were analyzed by differential scanning calorimetry (DSC) and grazing incidence wide angle X-ray scattering (GIWAXS). DSC revealed that a change in the nucleation process occurred from heterogeneous nucleation for bulk samples to homogeneous nucleation for infiltrated PBA and to surface-induced nucleation for infiltrated PBS. GIWAXS results indicate that PBS nanofibers crystallize in the α-phase, as well as their bulk samples. However, PBA nanofibers crystallize just in the β-phase, whereas PBA bulk samples crystallize in a mixture of α- and β-phases. The crystal orientation within the pores was determined, and differences between PBS and PBA were also found. Finally, broadband dielectric spectroscopy was applied to study the segmental dynamics for bulk and infiltrated samples. The glass temperature was found to significantly decrease in the PBS case upon infiltration, while that of PBA remained unchanged. These differences were correlated with the higher affinity of PBS to the AAO walls than PBA, in accordance with their nucleation behavior (surface-induced versus homogeneous nucleation, respectively). Tue, 26 Nov 2019 00:00:00 GMT http://hdl.handle.net/10366/169483 2019-11-26T00:00:00Z http://hdl.handle.net/10366/169465 [EN]Large bone defects are a significant health problem today with various origins, including extensive trauma, tumours, or congenital musculoskeletal disorders. Tissue engineering, and in particular bone tissue engineering, aims to respond to this demand. As such, we propose a specific model based on Elastin-Like Recombinamers-based click-chemistry hydrogels given their high biocompatibility and their potent on bone regeneration effect conferred by different bioactive sequences. In this work we demonstrate, using biochemistry, histology, histomorphometry and imaging techniques, the biocompatibility of our matrix and its potent effect on bone regeneration in a model of bone parietal lesion in female New Zealand rabbits. Fri, 30 Aug 2024 00:00:00 GMT http://hdl.handle.net/10366/169465 2024-08-30T00:00:00Z http://hdl.handle.net/10366/169463 [EN]The field of biomedicine relies on the development of advanced systems that mimic the extracellular matrix (ECM) to allow in vitro studies of cell–matrix interactions and subsequent implementation in vivo. The principalmatrices for biomedical applications are hydrogels, which are hydrophilic polymer networks that can absorb a large volume of water in resemblance to natural tissues (see Chapter 1). The materials used to obtain these biomimetic scaffolds include a large variety of synthetic polymers such as polyethylene glycol (PEG), as well as biopolymers, mostly proteins from animal tissues such as collagen (see Chapter 2). Combinations of natural and synthetic polymers have also been tested to improve the properties of hydrogels. Essential characteristics for the development of hydrogels for general biomedical applications include (i) an ability to provide a structural support to the surrounding cells, thus promoting natural and adequate cell growth that helps complete integration of the scaffold into the natural surrounding tissue and provides mechanical stability, (ii) an ability to mimic the ECM topography of tissues, (iii) an ability to mimic the natural environment so that cells can develop their normal functions and help restore damaged tissue, (iv) an ability to absorb and retain large quantities of water while maintaining their structures, thereby maintaining the hydration levels found in most tissues, (v) an ability to modulate their structures to match the shape and the size of defects, (vi) an ability to be easily manipulated, and, particularly, (vii) biocompatibility and biodegradability. Depending on the final application, hydrogels for use in regenerative medicine will need specific requirements in order to simulate the tissue to be repaired, such as cell adhesion or growth factors, which could also be included in the scaffold. Sat, 01 Jan 2022 00:00:00 GMT http://hdl.handle.net/10366/169463 2022-01-01T00:00:00Z http://hdl.handle.net/10366/169459 [EN]Despite lacking cooperatively folded structures under native conditions, numerous intrinsically disordered proteins (IDPs) nevertheless have great functional importance. These IDPs are hybrids containing both ordered and intrinsically disordered protein regions (IDPRs), the structure of which is highly flexible in this unfolded state. The conformational flexibility of these disordered systems favors transitions between disordered and ordered states triggered by intrinsic and extrinsic factors, folding into different dynamic molecular assemblies to enable proper protein functions. Indeed, prokaryotic enzymes present less disorder than eukaryotic enzymes, thus showing that this disorder is related to functional and structural complexity. Protein-based polymers that mimic these IDPs include the so-called elastin-like polypeptides (ELPs), which are inspired by the composition of natural elastin. Elastin-like recombinamers (ELRs) are ELPs produced using recombinant techniques and which can therefore be tailored for a specific application. One of the most widely used and studied characteristic structures in this field is the pentapeptide (VPGXG)n . The structural disorder in ELRs probably arises due to the high content of proline and glycine in the ELR backbone, because both these amino acids help to keep the polypeptide structure of elastomers disordered and hydrated. Moreover, the recombinant nature of these systems means that different sequences can be designed, including bioactive domains, to obtain specific structures for each application. Some of these structures, along with their applications as IDPs that self-assemble into functional vesicles or micelles from diblock copolymer ELRs, will be studied in the following sections. The incorporation of additional order- and disorder-promoting peptide/protein domains, such as α-helical coils or β-strands, in the ELR sequence, and their influence on self-assembly, will also be reviewed. In addition, chemically cross-linked systems with controllable order-disorder balance, and their role in biomineralization, will be discussed. Finally, we will review different multivalent IDPs-based coatings and films for different biomedical applications, such as spatially controlled cell adhesion, osseointegration, or biomaterial-associated infection (BAI). Sat, 01 Jan 2022 00:00:00 GMT http://hdl.handle.net/10366/169459 2022-01-01T00:00:00Z http://hdl.handle.net/10366/169455 [EN]Porous biomaterials are of significant interest in a variety of biomedical applications as they enable the diffusion of nutrients and gases as well as the removal of metabolic waste from implants. Pores also provide 3D spaces for cell compartmentalization and the development of complex structures such as vasculature and the extracellular matrix. Given the variation in the extracellular matrix composition across and within different tissues, it is necessary to tailor the physicochemical characteristics of biomaterials and or surfaces thereof for optimal bespoke applications. In this regard, different synthetic and natural polymers have seen increased usage in the development of biomaterials and surface coatings; among them, elastin-like polypeptides and their recombinant derivatives have received increased advocacy. The modular assembly of these molecules, which can be controlled at a molecular level, presents a flexible platform for the endowment of bespoke biomaterial properties. In this review, various elastin-like recombinamer–based porous biomaterials for both soft and hard tissue applications are discussed and their current and future applications evaluated. Fri, 01 Jan 2021 00:00:00 GMT http://hdl.handle.net/10366/169455 2021-01-01T00:00:00Z http://hdl.handle.net/10366/169428 [EN]This study evaluates the microstructure, porosity, mechanical properties and corrosion resistance of Ti-6Al-4V hip implant samples manufactured by Selective Laser Melting (SLM) and Electron Beam Melting (EBM), followed by different post-treatments (heat treatment and hot isostatic pressing -HIP-). Hydroxyapatite (HA) coatings were applied to enhance biocompatibility. Post-treated samples exhibited a lamellar α + β microstructure, with the EBM sample showing a coarser Widmanstätten structure, while acicular α' martensite was predominant in the as-built sample. The degree of porosity was lower than 0.2% in all samples. Microhardness was highest in the as-built sample (~ 400 HV) and lower in post-treated samples (~ 370 HV). Open Circuit Potential (OCP) tests indicated superior corrosion resistance for heat-treated samples, confirmed by Electrochemical Impedance Spectroscopy (EIS), where Sample E-HIP (HIP) showed a polarization resistance (Rpol) of 2490 kΩ/cm². In vitro tests confirmed that HA-coated samples exhibited excellent biocompatibility, slightly surpassing the Ti-6Al-4V samples. The HA-coated samples exhibited increased metabolic activity over 7 days, indicating superior biocompatibility. Finally, additive manufacturing combined with heat treatments and HA coatings effectively enhances Ti-6Al-4V for orthopaedic implants by improving the mechanical performance, corrosion resistance and biocompatibility. Wed, 23 Apr 2025 00:00:00 GMT http://hdl.handle.net/10366/169428 2025-04-23T00:00:00Z http://hdl.handle.net/10366/169001 [EN]Immune checkpoint inhibitors (ICIs) have improved cancer treatment; however, their use can be limited by immune-mediated adverse events, such as kidney damage. Diagnostic limitations of nephrotoxicity may lead to worsening of the patient's prognosis. This study aimed to validate a panel of urinary biomarkers as diagnostic tools for kidney damage in patients treated with ICIs. A prospective study was conducted on patients scheduled to receive ICIs. Those who subsequently developed kidney damage were considered cases; and those who did not were considered controls. A battery of biomarkers was assessed in urine samples at PRE-1, before the first treatment cycle; PRE-3, before the third cycle; and POST-3, 1 week after the third treatment cycle. A total of 46 patients participated in the study. At PRE-1, increased urinary excretion of IGFBP7, NAG, TIMP-2 × IGFBP7, and transferrin was observed in the case group, suggesting that these markers could be useful for early risk stratification of developing kidney damage. Furthermore, increased urinary excretion of albumin and NGAL was observed at PRE-3, suggesting that these markers could be of diagnostic utility to identify patients that could develop kidney damage once treatment is initiated. All of the aforementioned biomarkers demonstrated significant discriminatory ability between cases and controls, as verified by ROC curve analysis. The proposed biomarker battery could be used as a preventive tool for decision-making in the management of oncology patients at risk for kidney damage associated with ICIs. Furthermore, its use would allow personalized adjustment of therapy that would minimize the probability of renal complications even before starting the first cycle of treatment. Fri, 24 Oct 2025 00:00:00 GMT http://hdl.handle.net/10366/169001 2025-10-24T00:00:00Z http://hdl.handle.net/10366/167989 [EN]Simultaneous administration of certain antihypertensive (renin-angiotensin system inhibitors and diuretics) and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a renal toxicity syndrome known as "triple whammy" acute kidney injury (TW-AKI), yet poorly characterized at the pathophysiological level, as no specific experimental model exists on which to conduct preclinical research. Herein, we generated and characterized a rat model of TW-AKI (0.7 mg/kg/day trandolapril +400 mg/kg/day ibuprofen +20 mg/kg/day furosemide). Double treatments involving the NSAID caused a subclinical acute kidney injury, as they reduced glomerular filtration rate to a significant but not sufficient extent to increase Crpl concentration. Only the triple treatment generated an overt AKI with increased Crpl provided that animals were under partial water ingestion restriction. Histological examination revealed no evidence of tissue renal injury, and no proteinuria or makers of renal damage were detected in the urine. These findings, along with a normal fractional excretion of sodium and glucose, indicated that these drug combinations produce a prerenal type of AKI. In fact, blood pressure and renal blood flow were also reduced (most markedly following the triple combination), although renal dysfunction was more pronounced than expected for the corresponding pressure drop, supporting a key pathological role of the interference with renal autoregulation mechanisms. In summary, prerenal TW-AKI only occurs when volemia is challenged (i.e., by furosemide in partially water-deprived animals) under the effects of renin-angiotensin system inhibitors and NSAIDs. This model will facilitate further pathophysiological knowledge for a better diagnosis and clinical handling of this syndrome. Mon, 27 Jul 2020 00:00:00 GMT http://hdl.handle.net/10366/167989 2020-07-27T00:00:00Z http://hdl.handle.net/10366/167893 [EN]Cisplatin is an effective chemotherapeutic drug whose clinical use and efficacy are limited by its nephrotoxicity, which affects mainly the renal tubules and vasculature. It accumulates in proximal and distal epithelial tubule cells and causes oxidative stress-mediated cell death and malfunction. Consequently, many antioxidants have been tested for their capacity to prevent cisplatin nephrotoxicity. In this study, we made a systematic review of the literature and meta-analyzed 152 articles, which tested the nephroprotective effect of isolated compounds or mixtures of natural origin on cisplatin nephrotoxicity in preclinical models. This meta-analysis identified the most effective candidates and examined the efficacy obtained by antioxidants administered by the oral and intraperitoneal routes. By comparing with a recent, similar meta-analysis performed on clinical studies, this article identifies a disconnection between preclinical and clinical research, and contextualizes, discusses, and integrates the existing preclinical information toward the optimized selection of candidates to be further explored (clinical level). Despite proved efficacy, this article discusses the barriers limiting the clinical development of natural mixtures, such as those in extracts from Calendula officinalis flowers and Heliotropium eichwaldii roots. On the contrary, isolated compounds are more straightforward candidates, among which arjunolic acid and quercetin stand out in this meta-analysis. Tue, 10 Nov 2020 00:00:00 GMT http://hdl.handle.net/10366/167893 2020-11-10T00:00:00Z http://hdl.handle.net/10366/167576 [EN]Nephrotoxicity, including electrolytic disorders and acute kidney injury (AKI), limits the clinical dosage and utility of platinated antineoplastics such as cisplatin. Cisplatin nephrotoxicity embodies a tubulopathy involving the medullary S2 and S3 segments of the proximal and the distal tubules. Higher dosage extends damage over the cortical S1 segment and intensifies overall injury. However, the standard diagnosis based on plasma creatinine as well as novel injury biomarkers lacks enough pathophysiological specificity. Further granularity in the detection of renal injury would help understand the implications of individual damage patterns needed for personalized patient handling. In this article, we studied the association of urinary ganglioside GM2 activator protein (GM2AP) with the patterns of tubular damage produced by 5 and 10 mg/kg cisplatin in rats. Our results show that GM2AP appears in the urine only following damage to the cortical segment of the proximal tubule. The information provided by GM2AP is not redundant with but distinct and complementary to that provided by urinary neutrophil gelatinase-associated lipocalin (NGAL). Similarly, treatment with 150 mg/kg/day gentamicin damages the renal cortex and increases GM2AP urinary excretion; whereas renal ischemia, which does not affect the cortex, has no effect on GM2AP. Because of the key role of the cortical proximal tubule in renal function, we contend GM2AP as a potential diagnostic biomarker to stratify AKI patients according to the underlying damage and follow their evolution and prognosis. Prospectively, urinary GM2AP may help grade the severity of platinated antineoplastic nephrotoxicity by forming part of a non-invasive liquid biopsy. Fri, 01 Nov 2024 00:00:00 GMT http://hdl.handle.net/10366/167576 2024-11-01T00:00:00Z http://hdl.handle.net/10366/167575 [EN]Accumulating evidence suggests that hyperuricemia is a pathological factor in the development and progression of chronic kidney disease. However, the potential benefit afforded by the control of uric acid (UA) is controversial. Individual studies show discrepant results, and most existing meta-analysis, especially those including the larger number of studies, lack a placebo or control group as they aim to compare efficacy between drugs. On these grounds, we performed a me-ta-analysis restricted to studies including the action of any anti-gout therapies referenced to a control or placebo arm. This approach allows for a clearer association between UA reduction and renal effect. Of the twenty-nine papers included, most used allopurinol and febuxostat and, therefore, solid conclusions could only be obtained for these drugs. Both were very effective in reducing UA, but only allopurinol was able to significantly improve glomerular filtration rate (GFR), although not in a dose-dependent manner. These results raised doubts as to whether it is the hypouricemic effect of anti-gout drugs, or a pleiotropic effect, what provides protection of kidney function. Accordingly, in a correlation study that we next performed between UA reduction and GFR improvement, no association was found, which suggests that additional mechanisms may be involved. Of note, most trials show large inter-individual response variability, probably because they included patients with heterogeneous phenotypes and pathological characteristics, including different stages of CKD and comorbidities. This highlights the need to sub classify the effect of UA-lowering therapies according to the pathological scenario, in order to identify those CKD patients that may benefit most from them. Systematic Review Registration: CRD42022306646 https://www.crd.york.ac.uk/prospero/. Tue, 26 Mar 2024 00:00:00 GMT http://hdl.handle.net/10366/167575 2024-03-26T00:00:00Z http://hdl.handle.net/10366/167574 [EN]Contrast-induced nephropathy (CIN) is a complication associated with the administration of contrast media (CM). The CIN diagnosis is based on creatinine, a biomarker late and insensitive. The objective proposed was to evaluate the ability of novel biomarkers to detect patients susceptible to suffering CIN before CM administration. The study was carried out with patients undergoing cardiac catheterization involving CM. Patients were divided into two groups: (1) CIN, patients who developed this pathology; (2) control, patients who did not suffer CIN. Prior to the administration of CM, urine samples were collected to measure proteinuria, N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, albumin, transferrin, t-gelsolin and GM2 ganglioside activator protein (GM2AP). The risk factors advanced age, low body mass index and low estimated glomerular filtration rate; and the urinary biomarkers albumin, transferrin and GM2AP showed significant predictive capacity. Of all of them, albuminuria demonstrated the highest diagnostic power. When a cutoff point was established for albuminuria at values still considered subclinical (10-30 µg/mg Cru), it was found that there was a high incidence of CIN (40-75%). Therefore, albuminuria could be applied as a new diagnostic tool to prevent and predict CIN with P4 medicine criteria, independently of risk factors and comorbidities. Tue, 26 Oct 2021 00:00:00 GMT http://hdl.handle.net/10366/167574 2021-10-26T00:00:00Z